A meta‐analysis of the association between vasopressor use and intensive care unit‐acquired weakness

Abstract Objective This study aims to clarify the uncertain association between vasopressor administration and the development of intensive care unit‐acquired weakness (ICUAW) in critically ill adult patients. Methods We conducted a comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials up to October 10, 2023. Titles and abstracts were independently screened by two authors, who then reviewed full texts and extracted relevant data from the studies that met the inclusion criteria. This review included prospective and retrospective cohort studies that explored the relationship between vasopressor use and ICUAW utilizing univariate or multivariate analysis in adult ICU patients. Results A total of 15 studies were included in our review, collectively indicating a statistically significant association between the use of vasopressors and the occurrence of ICUAW (odds ratio [OR], 3.43; 95% confidence intervals [CI], 1.95–6.04), including studies utilizing multivariate analysis (OR, 3.43; 95% CI, 1.76–6.70). Specifically, the use of noradrenaline was significantly associated with ICUAW (OR, 4.42; 95% CI, 1.69–11.56). Subgroup and sensitivity analyses further underscored the significant relationship between vasopressor use and ICUAW, particularly in studies focusing on patients with clinical weakness, varying study designs, different sample sizes, and relatively low risk of bias. However, this association was not observed in studies limited to patients with abnormal electrophysiology. Conclusions Our review underscores a significant link between the use of vasopressors and the development of ICUAW in critically ill adult patients. This finding helps better identify patients at higher risk of ICUAW and suggests considering targeted therapies to mitigate this risk.


INTRODUCTION
Intensive care unit-acquired weakness (ICUAW) represents a prevalent neuromuscular complication in patients experiencing critical illnesses.This condition is notably linked with prolonged mechanical ventilation, escalated healthcare expenditures, extended durations in both intensive care unit (ICU) and hospital settings, and an increase in ICU-and hospital-related mortality rates (Hermans et al., 2014;Nguyen The & Nguyen Huu, 2015;Peñuelas et al., 2018).Septic shock, a significant public health concern, is characterized by elevated mortality and morbidity (Rhodes et al., 2017).In this context, vasopressor therapy emerges as a cornerstone in managing critically ill patients with septic shock (Evans et al., 2021).The incidence of ICUAW is high among this patient population; however, the precise relationship between vasopressor administration and the development of ICUAW remains to be elucidated.The potential adverse effects of vasopressors, particularly concerning ICUAW onset, have garnered considerable attention from researchers and clinicians alike.Although some clinical trials suggest a statistically notable correlation between vasopressor use and ICUAW development, others report no such association.This systematic review and meta-analysis aim to synthesize data from prospective and retrospective cohort studies to rigorously evaluate the association between vasopressor utilization and the emergence of ICUAW.

METHODS
This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement (Moher et al., 2009).

Search strategy
The following databases were searched for pertinent English language studies from inception through October 10, 2023: PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials.We used specific search terms for PubMed (Supporting Information) and adapted them for the other databases.Additionally, we performed a manual search of references cited by the included articles and relevant review articles to identify other eligible studies.

Selection criteria
The inclusion criteria were as follows: prospective and retrospective cohort studies in adult patients (age >18) that evaluated the use of vasopressors and the incidence of ICUAW utilizing univariate or multivariate analysis; diagnoses of ICUAW (Fan et al., 2014;Stevens et al., 2009)

Study selection and data abstraction
Two reviewers (T.Y. and Y.W.) independently reviewed studies based on the inclusion criteria.They also independently extracted the following data from each study using a standardized data collection form: author

Study quality assessment
Two reviewers (T.Y. and Y.W.) independently assessed the methodological quality of each study using the Newcastle-Ottawa scale (Higgins & Green, 2015) and the Quality Assessment Tool for Diagnosis Accuracy Studies (QUADAS-2) (Whiting et al., 2003).

Data analysis
The meta-analysis was performed using Stata version 15.0 (StataCorp), and the results were analyzed using odds ratios (ORs) and 95% confidence intervals (CIs).The DerSimonian and Laird random effects model was used for data analyses.Heterogeneity was assessed using the χ 2 statistic with p ≤ .1 considered statistically significant.The impact of statistical heterogeneity on the study results was estimated by calculating the I 2 statistic.Values of the I 2 statistic above 50% were regarded as a cutoff point for considerable heterogeneity.Subgroup analyses examined (1) studies using clinical muscle testing and electrophysiology as diagnostic methods; (2) studies with relatively large sample sizes (excluding studies with a sample size less than 100); and (3) prospective and retrospective cohort studies.The sensitivity analysis examined studies with a relatively low risk of bias (excluding studies with a Newcastle-Ottawa scale score <7).We examined publication bias using Begg's rank correlation test for quantitative assessment and funnel plots for qualitative assessment.

Vasopressors and ICUAW
When the data from 15 studies were combined, as shown in Figure 3, the analysis found a notable association between the use of vasopressors and the occurrence of ICUAW.The OR was 3.43 with a 95% CI of 1.95-6.04,indicating a statistically significant result (p < .01).To address the heterogeneity in the data, a random effects model was applied (τ 2 = .90;χ 2 = 74.83,df = 14; p < .01;I 2 = 81.3%).This analysis revealed that the incidence of ICUAW was substantially higher in patients treated with vasopressors (50.1%) compared to those in the control group (27.4%).
Furthermore, when the results from nine studies utilizing multivariate analysis to determine the relationship between vasopressor use and ICUAW were combined, as shown in Table 3, the analysis also found a significant association between the use of vasopressors and the occurrence of ICUAW.The OR was 3.43 with a 95% CI of 1.76-6.70,indicating a statistically significant result (p < .01).To address the heterogeneity in the data, a random effects model was applied (τ 2 = .78; χ 2 = 45.17,df = 8; p < .01;I 2 = 82.3%).This analysis revealed that the incidence of ICUAW was substantially higher in patients treated with vasopressors (50.3%) compared to those in the control group (27.6%).

Clinical assessment versus electrophysiology
The subgroup analyses, detailed in

F I G U R E 2
The quality outcomes of the included studies.

Heterogeneity
The analysis identified methodological heterogeneity across the included studies, attributed to variations in diagnostic methods, study design types, and sample sizes.The studies employed either clinical assessment or electrophysiology for diagnoses and were categorized as either prospective or retrospective cohort studies.Furthermore, studies were classified based on sample size, with a cutoff of 100 subjects distinguishing small from large studies.This methodological diversity necessitated three distinct comparisons within the review: clinical assessment versus electrophysiology, prospective versus retrospective studies, and analysis based on sample size (n ≥ 100 vs. n < 100).
Given the high levels of statistical heterogeneity observed within each comparison, a random-effects model was deemed more appropriate than a fixed-effects model to adequately address the heterogeneity.

Assessment of publication biases
Publication bias was evaluated using funnel plots, as illustrated in

DISCUSSION
This comprehensive review sheds light on the intricate relationship between the use of vasopressors and the development of ICUAW, underlining the significance of vasopressor administration as a notable risk factor for ICUAW.Amid the backdrop of sepsis and septic shock being predominant contributors to healthcare costs and mortality in hospital settings, the role of hemodynamic stabilization emerges as a critical component in managing patients with sepsis or septic shock.
This involves initial fluid administration followed by the administration of vasoactive agents in cases of persistent circulatory shock.Despite adequate fluid resuscitation, the necessity for vasopressors to either restore or maintain an optimal mean arterial pressure (MAP) is evident (Vincent, 2022), with current guidelines (Evans et al., 2021) advocating for a target MAP of at least 65 mmHg in patients unresponsive to initial fluid therapy.The variable impact of vasopressors on regional, systemic, and organ perfusion is acknowledged, positing a potential pathophysiological pathway to ICUAW through the diminution of microcirculation (Boerma & Ince, 2010;Di Giantomasso et al., 2003, 2005).This reduction in microcirculation may precipitate bioenergetic failure, culminating in ischemic muscle fiber injury (Boërio et al., 2018;Friedrich et al., 2015).Norepinephrine, recognized as the first-line vasopressor for shock management, is associated with lower mortality rates and fewer adverse effects (Colling et al., 2018;Evans et al., 2021), yet its correlation with an increased risk of developing ICUAW underscores a critical area of concern.This association is further supported by animal studies suggesting that the elevation of MAP with norepinephrine during resuscitation may exacerbate sepsis-induced muscle damage, likely through impaired microcirculation and consequent ischemic risk to muscle tissues (Boërio et al., 2018).Vasopressors are used as a potentially life-saving treatment in patients at high shortterm risk of death from shock.Although it is vitally important to study the long-term effects of the treatments provided in the ICU, the reason is to help us better identify patients at risk of developing these effects.In the case of ICUAW, clarifying that vasopressor use is a true risk factor for ICUAW may help us better identify patients at higher risk and consider providing targeted therapies aimed at mitigating this risk.
There have been studies (Anekwe et al., 2020;Rosa et al., 2023;Wang et al., 2022) suggesting that early activity, rehabilitation training, and functional recovery exercise in severe patients can promote the synthesis of muscle protein, reduce the catabolism of muscle protein, and enhance muscle strength, which is effective in preventing the occurrence and development of ICUAW, and the earlier the intervention, the better the effect.There have also been studies (Liu et al., 2020;Zhou et al., 2022)  This result partly demonstrates the stability of the overall effect size.
The review's robustness is evident in subgroup analyses across various dimensions, including sample sizes and study designs, affirming a consistent association between vasopressor use and ICUAW.However, the review is not without limitations.No randomized controlled trials met the inclusion criteria, which diminishes the strength of evidence and recommendations.High levels of heterogeneity were identified for all of the outcomes.We analyzed the outcomes in subgroups classified by study design, diagnostic methods, and sample sizes in an effort to reduce methodological and clinical heterogeneity; however, substantial statistical heterogeneity remained despite these attempts.

CONCLUSION
This review conclusively demonstrates a statistically significant association between the use of vasopressors, particularly noradrenaline, Note: Y-criteria satisfied, N-criteria not satisfied.

Figure 4 ,
Figure4, which did not exhibit significant asymmetry, suggesting an absence of publication bias.Begg's test further supported this finding (Z = 1.78; p = .08),indicating no significant publication biases in the meta-analysis.
demonstrating that early enteral nutrition can inhibit the excessive immune response and reduce the incidence of ICUAW.Subgroup analyses illuminate a significant correlation between vasopressor usage and muscle weakness, particularly in patients presenting with clinical weakness as opposed to those identified through abnormal electrophysiology.This distinction underscores the utility of clinical examinations in diagnosing ICUAW, despite potential limitations in early disease stages due to suboptimal patient consciousness or attentiveness.The sensitivity of electrophysiological studies in detecting subclinical ICUAW introduces an alternative explanation for the disparate outcomes observed between subgroups.Our subgroup analyses revealed that studies limited to different sample sizes, prospective or retrospective cohort, and relatively low risk of bias still demonstrated a significant association between vasopressor use and ICUAW.
and the incidence of ICUAW.It underscores the importance for ICU medical teams to coordinate multidisciplinary care to optimize rehabilitation delivery, nutritional support, and early mobilization protocols in patients undergoing vasopressor treatment.Future research should focus on elucidating the mechanisms underlying skeletal muscle dysfunction in patients using vasopressors and developing interventions to mitigate ICUAW.
that utilized noradrenaline, a significant link was observed between its use and an increased likelihood of ICUAW development.The effect size, with an OR of 4
TA B L E 3 , I-squared statistic test for heterogeneity; NOS, the Newcastle-Ottawa scale score; OR, odds ratio; Pe, p value for the effect estimate for each subgroup; Ph, p value for test of heterogeneity.